Lesion-associated microglia and macrophages react with massive phagocytosis for debris clearance and wound healing after LPS-induced dopaminergic depletion

Abstract Background Neuroinflammation contributes to neuronal degeneration in Parkinson’s disease (PD). However, how brain inflammatory factors mediate the progression of neurodegeneration is still poorly understood. Experimental models of PD have shed light on the understanding of this phenomenon, but the exploration of inflammation-driven models is necessary to better characterize this aspect of the disorder. The use of lipopolysaccharide (LPS) to induce a neuroinflammation-mediated neuronal loss is useful to induce reliable elimination of dopaminergic neurons. Nevertheless, how this model parallels the PD-like neuroinflammation is uncertain.Methods In the present work, we used the direct LPS stereotactic injection as a model inductor to eliminate dopaminergic neurons of the substantia nigra pars compacta (SNpc) in rats and reevaluated the microanatomy of inflammatory reaction three and seven days after the insult. For this, we analyzed the tissue with high resolution confocal microscopy to assess the neuronal loss, the vulnerability of dopaminergic neurons, as well as the activation of lesion-associated microglia and macrophages (LAMMs) together with the visualization of their phagocytic capacity. In addition, we set up a co-culture of BV2 microglia and PC12 dopaminergic cells to understand the role of LPS-mediated neuroinflammatory toxicity versus phagocytosis.Results High-resolution 3D histological examination revealed that, although LPS induced a reliable elimination of SNpc dopaminergic neurons, it also generated a massive neuroinflammatory response. This inflammation-mediated injury was characterized by a damaged parenchyma occupied by a vast population of LAMMs undertaking wound compaction and scar formation. LAMMs tiled the entire lesion and engaged in long-standing phagocytic activity to resolve the injury. Additionally, modeling LPS inflammation in a cell culture system helped to understand the role of phagocytosis and cytotoxicity in dopaminergic degeneration and indicated that LAMM-mediated toxicity and phagocytosis coexist during LPS-mediated dopaminergic elimination.Conclusions This type of severe inflammatory-mediated injury appears to be different from the ageing-related PD scenario where the architectural structure of the parenchyma is preserved. Thus, the necessity to explore new experimental models to properly mimic the inflammatory compound observed in PD degeneration.